Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein.

In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer from non-motor symptoms, including early cognitive and social impairment, that do not respond well to dopaminergic therapy. Cholinergic deficits may contribute to these problems, but cholinesterase inhibitors have limited efficacy. Mice over-expressing α-synuclein, a protein critically associated with PD, show deficits in cognitive and social interaction tests, as well as a decrease in cortical acetylcholine. We have evaluated the effects of chronic administration of nicotine in mice over-expressing wild type human α-synuclein under the Thy1-promoter (Thy1-aSyn mice). Nicotine was administered subcutaneously by osmotic minipump for 6 months from 2 to 8 months of age at 0.4 mg/kg/h and 2.0 mg/kg/h. The higher dose was toxic in the Thy1-aSyn mice, but the low dose was well tolerated and both doses ameliorated cognitive impairment in Y-maze performance after 5 months of treatment. In a separate cohort of Thy1-aSyn mice, nicotine was administered at the lower dose for one month beginning at 5 months of age. This treatment partially eliminated the cognitive deficit in novel object recognition and social impairment. In contrast, chronic nicotine did not improve motor deficits after 2, 4 or 6 months of treatment, nor modified α-synuclein aggregation, tyrosine hydroxylase immunostaining, synaptic and dendritic markers, or microglial activation in Thy1-aSyn mice. These results suggest that cognitive and social impairment in synucleinopathies like PD may result from deficits in cholinergic neurotransmission and may benefit from chronic administration of nicotinic agonists.

Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington's Disease Mice.

Huntington's disease (HD) is an inherited neurodegenerative disorder with no disease-modifying treatment. Expansion of the glutamine-encoding repeat in the Huntingtin (HTT) gene causes broad effects that are a challenge for single treatment strategies. Strategies based on human stem cells offer a promising option. We evaluated efficacy of transplanting a good manufacturing practice (GMP)-grade human embryonic stem cell-derived neural stem cell (hNSC) line into striatum of HD modeled mice. In HD fragment model R6/2 mice, transplants improve motor deficits, rescue synaptic alterations, and are contacted by nerve terminals from mouse cells. Furthermore, implanted hNSCs are electrophysiologically active. hNSCs also improved motor and late-stage cognitive impairment in a second HD model, Q140 knockin mice. Disease-modifying activity is suggested by the reduction of aberrant accumulation of mutant HTT protein and expression of brain-derived neurotrophic factor (BDNF) in both models. These findings hold promise for future development of stem cell-based therapies.

Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington's disease.

BACKGROUND: No disease modifying treatment currently exists for Huntington's disease (HD), a fatal neurodegenerative disorder characterized by the formation of amyloid-like aggregates of the mutated huntingtin protein. Curcumin is a naturally occurring polyphenolic compound with Congo red-like amyloid binding properties and the ability to cross the blood brain barrier. CAG140 mice, a knock-in (KI) mouse model of HD, display abnormal aggregates of mutant huntingtin and striatal transcriptional deficits, as well as early motor, cognitive and affective abnormalities, many months prior to exhibiting spontaneous gait deficits, decreased striatal volume, and neuronal loss. We have examined the ability of life-long dietary curcumin to improve the early pathological phenotype of CAG140 mice. RESULTS: KI mice fed a curcumin-containing diet since conception showed decreased huntingtin aggregates and increased striatal DARPP-32 and D1 receptor mRNAs, as well as an amelioration of rearing deficits. However, similar to other antioxidants, curcumin impaired rotarod behavior in both WT and KI mice and climbing in WT mice. These behavioral effects were also noted in WT C57Bl/6 J mice exposed to the same curcumin regime as adults. However, neither locomotor function, behavioral despair, muscle strength or food utilization were affected by curcumin in this latter study. The clinical significance of curcumin's impairment of motor performance in mice remains unclear because curcumin has an excellent blood chemistry and adverse event safety profile, even in the elderly and in patients with Alzheimer's disease. CONCLUSION: Together with this clinical experience, the improvement in several transgene-dependent parameters by curcumin in our study supports a net beneficial effect of dietary curcumin in HD.

Selective blockade of serotonin 2C receptor enhances Fos expression specifically in the striatum and the subthalamic nucleus within the basal ganglia.

Serotonin(2C) (5-HT(2C)) receptors are widely expressed in the basal ganglia, a group of brain regions involved in the control of motor behavior. However, it remains unclear whether their tonic influence on neuronal activity is distributed in these regions. We have addressed this question by measuring the product of the proto-oncogene c-Fos in rats after peripheral administration of the non-selective 5-HT antagonist mianserin, the 5-HT(2C/2B) antagonist SER-082 or the selective 5-HT(2C) antagonist SB 243213. The intraperitoneal administration of 1mg/kg of SB 243213 or SER-082, but not mianserin, enhanced Fos-immunoreactive cells in the subthalamic nucleus and the striatum, primarily its medial portion. None of these treatments significantly affected Fos expression in the external globus pallidus, the entopeduncular nucleus (the internal globus pallidus in primate) or the substantia nigra pars reticulata. The data suggest that selective blockade of 5-HT(2C) receptors is necessary to unmask a tonic regulation of neuronal activity by this receptor in the basal ganglia and that this effect is restricted to the two structures receiving cortical entries, the striatum and the subthalamic nucleus.

The biological sciences section program at the 60th Annual Meeting of the Gerontological Society of America.

In this era of genomics and other exciting technical advances, research on the biology of aging is undergoing a renaissance. This report summarizes 10 cutting-edge areas of research covered in symposia that spanned such topics as stem cells, novel vaccine strategies, nutritional sensing, new concepts of Parkinson's disease, high throughput screening for aging interventions, manipulating telomerase in cancer and immunodeficiency, synergy between aging and HIV disease, and epigenetic influences on aging. Novel animal models, including those showing no evidence of aging, as well as ethical and political implications of embryonic stem cells and alternative medicine are also discussed.

Effects of antioxidants on cancer prevention and neuromotor performance in Atm deficient mice.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by immunodeficiency, neurodegeneration and cancer. The disease results from bi-allelic mutations in the AT mutated (ATM) gene involved in cell cycle checkpoint control and repair of DNA double-strand breaks. Evidence has been accumulating that oxidative stress is associated with AT and may be involved in the pathogenesis of the disease. This led to a hypothesis that antioxidants may alleviate the symptoms of AT. Consequently, several studies were conducted in Atm deficient mice to examine the role of antioxidants in cancer prevention and/or correction of neuromotor performance. N-acetyl-l-cysteine (NAC), EUK-189, tempol, and 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) have been tested in Atm deficient mice. In contrast to other antioxidants, NAC has been used in the clinical practice for many decades and is available as a dietary supplement. In this article, we review chemoprevention studies in Atm deficient mice and, in more detail, our findings on the effect of NAC. Our short-term study showed that NAC suppressed genome rearrangements linked to cancer. The long-term study demonstrated that NAC reduced the incidence and multiplicity of lymphoma and improved some aspects of motor performance.

Behavioral phenotypes and pharmacology in genetic mouse models of Parkinsonism.

Prior to the discovery of genes associated with familial forms of Parkinson's disease, animal models of Parkinson's disease mainly consisted of toxin models based exclusively on the degeneration of nigrostriatal dopamine neurons. These traditional models have provided valuable insight into symptomatic treatments for Parkinson's disease; however, they lack the broad extra-nigral pathology and the progression that is observed in the disease. The novel genetic mouse models recently generated are advantageous because they have mutations that are known to cause familial Parkinson's disease and thus they have good construct validity. To maximize the utility of these models, a thoughtful phenotypical characterization is important. Our laboratory has assembled a battery of behavioral tests to assess sensorimotor function in genetic mouse models of Parkinsonism. This review discusses the sensitivity of these tests in different genetic mice in addition to their behavioral response to dopamine agonists.

Transplantation of multipotent cells extracted from adult skeletal muscles into the subventricular zone of adult rats.

Stem cells isolated from adult tissues may be useful for autologous cell therapy in the nervous system. In the present study we tested the ability of multipotent stem cells isolated from adult muscle to survive and respond to migratory and differentiating cues when transplanted into the adult subventricular zone (SVZ). Prior to transplantation the cells were grown as spheres that expressed doublecortin, nestin, and betaIII-tubulin, as well as the mRNAs for the receptor EphA4 and the ligands ephrin B1, ephrin B2, but not ephrin B3. Four weeks after transplantation into the anterior part of the SVZ in adult rats, surviving cells were observed along the ventricular wall, in the SVZ, and in the posterior rostral migratory stream (RMS). None of these cells stained for betaIII-tubulin or doublecortin, which are molecules expressed by migrating neuroblasts, and none were present in the more rostral regions of the RMS or the olfactory bulb. However, most surviving transplanted cells were integrated into the wall of the lateral ventricle and expressed vimentin, a marker also expressed by ependymocytes. No tumors were observed 4 weeks posttransplantation. Our results suggest that multipotent stem cells isolated from adult muscle, which can be easily and safely isolated from patients and rapidly expanded ex vivo, may provide autologous vectors for the local delivery of secreted factors to the ventricles or nearby regions.

Vascular changes in the subventricular zone after distal cortical lesions.

One of the effects of cortical lesions is to produce cell proliferation in the subventricular zone (SVZ), a neurogenic zone of the adult brain distal from the lesion. The mechanisms of these effects are unknown. Recent evidence points to a relationship between the vasculature and neurogenesis both in vitro and in vivo. In the present study, we asked whether cortical lesions induced vascular modifications in the distal SVZ in vivo. Lesions of the frontoparietal cortex were produced by thermocoagulation of pial blood vessels, a method that leads to highly reproducible loss of all cortical layers, sparing the corpus callosum and underlying striatum. These lesions induced increased immunoreactivity for vascular endothelial growth factor (VEGF) around the walls of SVZ vessels, at a considerable distance from the lesion. Vascular permeability was markedly increased in both the SVZ and RMS by 3 days after the injury. A dramatic increase in endothelial proliferation was followed by expansion of the local SVZ vascular tree 7 days after the injury. This time course corresponded to the proliferative changes in the SVZ, and a tight correlation was observed between the number of blood vessels and the increase in SVZ cell number. The data demonstrate that thermocoagulatory cortical lesions induce distal vascular changes that could play a role in lesion-induced SVZ expansion.

Genetic mouse models of parkinsonism: strengths and limitations.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Patients with PD display a combination of motor symptoms including resting tremor, rigidity, bradykinesia, and postural instability that worsen over time. These motor symptoms are related to the progressive loss of dopamine neurons in the substantia nigra pars compacta. PD patients also suffer from nonmotor symptoms that may precede the cardinal motor symptoms and that are likely related to pathology in other brain regions. Traditional toxin models of PD have focused on the nigrostriatal pathway and the loss of dopamine neurons in this region, and these models have been important in our understanding of PD and in the development of symptomatic treatments for the disease. However, they are limited in that they do not reproduce the full pathology and progression seen in PD, thus creating a need for better models. The recent discovery of specific genes causing familial forms of PD has contributed to the development of novel genetic mouse models of PD. This review discusses the validity, benefits, and limitations of these new models.

Adult reserve stem cells and their potential for tissue engineering.

Tissue restoration is the process whereby multiple damaged cell types are replaced to restore the histoarchitecture and function to the tissue. Several theories have been proposed to explain the phenomenon of tissue restoration in amphibians and in animals belonging to higher orders. These theories include dedifferentiation of damaged tissues, transdifferentiation of lineage-committed progenitor cells, and activation of reserve precursor cells. Studies by Young et al. and others demonstrated that connective tissue compartments throughout postnatal individuals contain reserve precursor cells. Subsequent repetitive single cell-cloning and cell-sorting studies revealed that these reserve precursor cells consisted of multiple populations of cells, including tissue-specific progenitor cells, germ-layer lineage stem cells, and pluripotent stem cells. Tissue-specific progenitor cells display various capacities for differentiation, ranging from unipotency (forming a single cell type) to multipotency (forming multiple cell types). However, all progenitor cells demonstrate a finite life span of 50 to 70 population doublings before programmed cell senescence and cell death occurs. Germ-layer lineage stem cells can form a wider range of cell types than a progenitor cell. An individual germ-layer lineage stem cell can form all cells types within its respective germ-layer lineage (i.e., ectoderm, mesoderm, or endoderm). Pluripotent stem cells can form a wider range of cell types than a single germ-layer lineage stem cell. A single pluripotent stem cell can form cells belonging to all three germ layer lineages. Both germ-layer lineage stem cells and pluripotent stem cells exhibit extended capabilities for self-renewal, far surpassing the limited life span of progenitor cells (50-70 population doublings). The authors propose that the activation of quiescent tissue-specific progenitor cells, germ-layer lineage stem cells, and/or pluripotent stem cells may be a potential explanation, along with dedifferentiation and transdifferentiation, for the process of tissue restoration. Several model systems are currently being investigated to determine the possibilities of using these adult quiescent reserve precursor cells for tissue engineering.